Conventionally, steroids and zinc oxide formulations have been topically used as medicines for treating skin diseases such as dermatitis, sunburn, neurodermatitis, eczema and anogenital pruritus. Steroids, however, have been difficult to administer in large quantities for a prolonged period due to their strong adverse side effects. Zinc oxide formulations, which have local astringent action, involve problems with respect to the manufacture of pharmaceuticals, since they are insoluble in water and are not usually administered internally.
In the meantime, developments in atomic energy have revolutionized many fields such as power generation, diagnoses of various diseases, and radiation therapy for the treatment of cancer. Radiotherapy, especially, raises a problem of side effects associated with radiation damage. These effects include early stage problems such as a decrease in the number of leukocytes, loss of hair and the flushing of skin, and late stage problems which may only be recognized after a long period of time, such as cartinogenesis, cataracts and fetal disorders. There are also systemic disorders due to acute exposure to radiation, for example, radiation sickness caused by atomic weapons and accidents in atomic power stations. Symptoms of nausea, anorexia, and a general weariness similar to a hangover are known as adverse side effects of radiation therapy ["Active Oxygen", Tsutomu KAGIYA, 334-360, published by Ishiyaku Shuppan K. K., 1987]. One of the causes of the above disorders is said to be an abnormal production of free radicals in the body due to exposure to radiation. However, as yet there have not been effective medicines for preventing these disorders or otherwise minimizing the effects of exposure to radiation.
On the other hand, in the field of cosmetic compositions, UV absorbers such as para-aminobenzoic acid derivatives, cinnamic acid derivatives, salicylic acid derivatives, camphor derivatives, urocanic acid derivatives, benzophenone derivatives and heterocyclic derivatives are incorporated into compositions exclusively for external use and used for purposes of preventing sunburn or the like. These UV absorbers suppress the formation of erythema of the skin and bulla, and are also employed for the purposes of preventing pigmentation by suppressing the formation of melanin and thereby preventing the aging of the skin.
There are two different types of dermatological reactions caused by sunlight, one is an acute inflammatory change in the skin called sunburn, and the other is a subsequent melanin pigmentation called suntan. The light having a wave length in the range of 320 nm or less, called UVB, induces sunburn and is responsible for erythematous change. The erythemic reaction caused by UV rays, as opposed to a burn injury, does not occur immediately after the exposure to the sunlight, but rather occurs after a latent period of several hours. When sunburned skin is histopathologically examined, various degrees of inflammatory changes are recognized in the epidermis and dermis depending on the dose of radiation. Among such changes, a notable one is the generation of so-called sunburn cells (SBC) in the epidermis. A histologically stained tissue sample presents strongly and acidophilically stained cells which have pyknotic nuclei. This phenomenon indicates the necrosis of epidermal cells ["Fragrance Journal", 9, 15-20 (1991)]. In order to prevent sunburn, para-aminobenzoic acid derivatives, cinnamic acid derivatives or the like UV absorbers mentioned above are used, but their UV absorbing effects are not necessarily satisfactory. What is more, they raise problems of cumbersome handling upon use, poor stability, low compatibility with other components of the composition, and also involve unsolved problems in water-resistance and oil-resistance.
In the field of medicines for the treatment of skin diseases, development of medicines which have minimal adverse side effects, and which have novel functions obtainable by both external and internal administrations has been desired. Also, in the field of the therapy and prevention of radiation disorders, medicines which can suppress and cure the disorders caused by oxidative reactions have been desired. Fastly, in the field of the manufacture of cosmetics, cosmetics which overcome the above-mentioned problems such as handling upon use and stability of the composition have been desired. Accordingly, the present invention is to provide therapeutic agents for treating skin diseases having the above-mentioned characteristics, induction of metallothionein, for suppressing the formation of sunburn cells, and for use in cosmetic compositions.
Zinc, one of the indispensable trace metals in the living body, is known to participate in the development of sexual organs, promotion of wound healing and is also known to be a component of a metalloenzyme, an accelerator for dehydrogenase, and to have various functions such as activating the immune system. Zinc is further known to be an inducing factor of metallothionein (MT), a metal-combining protein. It is reported that MT functions as a scavenger of free radicals which are generated at the onset of inflammations ["Dermatologica", Hanada, k., et al., 179 (suppl. 1) 143 (1989)].
The present inventors considered that, in dermatological inflammations caused by external irritative stimulants, such as sunburn or the like, MT could act to quench the free radicals released from leukocytes, especially granulocytes which gather at the inflamed region, and thereby exhibit an anti-oxidation action to diminish cell damage, especially to normal lymphocytes, to activate the immune system and further to prevent the accelerated aging of the skin. They further considered that the formation of sunburn cells (SBCs) could be suppressed by administering zinc for inducing MT to be present, or to increase MT in the epidermal keratinous layer. They furthermore considered that MT's anti-oxidation action can also be useful in the treatment of skin problems resulting from radiation therapy by X rays, alpha rays, beta rays, gamma rays, neutron rays and accelerated electron rays.
In the above situation, the present inventors have studied various zinc compounds with respect to their pharmacological activities, and have found that zinc salts or zinc complexes of a certain compound have an unexpected and excellent action of inducing MT and suppressing SBC production due to UV rays, and thereby useful as components of cosmetic compositions or medicines for purposes of ameliorating sunburn, preventing sunburn, ameliorating sufferings from skin diseases and ameliorating other radiation induced disorders, leading to completion of the invention.